: This grant application proposes to study the mechanism through which the RET/PTC oncogenes induce papillary thyroid cancer. While the mechanism of RET activation of cell signaling pathways has been evaluated in a variety of cells, almost nothing is known about its signaling pathways in the thyroid, where it is normally expressed. Considering that RET is intimately involved in carcinogenesis, both for differentiated thyroid tumors and medullary thyroid tumors, this study has a very sensible goal. In particular, the applicant will study the effects of RET/PTC on cell cycle control and genomic stability, evaluate signaling of RET/PTC through the RAS pathway and via PLC-gamma and determine the role of PKC-epsilon in thyroid cell transformation in vivo. RET/PTC rearrangements (four or more) are unique to papillary thyroid carcinoma, and RET/PTC3 is especially prevalent in cancers arising in children exposed to radiation in Chernobyl. RET/PTC appears to be a specific initiating event in tumorigenesis, although presumably with additional mutational change. The translocations forming the RET/PTC oncogene appear to be through chromosomal exchange at specific break points, and it is suggested that these are because the sites of exchange are next to each other during interphase. RET/PTC is believed to be constitutively activated, and that phosphorylation at position 586 allows binding to the membrane and interaction with SHC, allowing it to transduce signals through RAS. Subsequent steps in the pathway may involve MAP kinase, or possibly phospholipase C-gamma. Studies on H-RAS have shown that it, when constitutively expressed, can act possibly through MAP kinases to cause abnormal mitosis. Activation of PLC-gamma can cause activation of PKC-epsilon, and this may possibly be involved in apoptosis.